Described here is a rapid screening method for identifying compounds having catalyst activity which employs mass spectrometric analysis. The method is exemplified for rapid screening of polymerization catalysts using tandem mass spectrometry and gas phase ion-molecule reactions and is specifically applied to screening of organometallic catalysts used in the production of polyolefins. The screening method of this invention has the advantages of high sensitivity (mg-scale quantities), very short assay times (one hour), simultaneous competitive screening of multiple catalysts directly according to propensity for high polymer formation (rather than a derivative property such as heat release), good prospects for scaling to large combinatorial libraries, and implicit encoding of catalyst identity by mass. Simple ion-molecule reactions are used to simplify the mass spectrum of complicated mixtures generated during screening.
The identification, preparation and testing of individual catalysts has been long pursued. The screening of catalyst libraries to identify new and improved catalysts is a recent phenomenon. Screening of libraries of compounds, which may have been combinatorially generated, has been extensively applied in biological systems and for the identification of potential therapeutic agents. Methods for high-throughput combinatorial screening of organometallic catalysts now occupy a central position in the emerging area of combinatorial materials science. (A general review of screening for catalysts has recently appeared: Jandeleit, B. et al. (1998) Cat. Tech. 2:101). A variety of strategies have been employed to implement catalyst screening by correlating some aspect of catalysis to a measurable quantity. Preferred screening strategies are those that are rapid and which can be applied to assess very small samples. Chromatographic (Francis, M. B. (1999) Angew. Chem. 111:987), thermographic (Taylor, S. J. and Morken, J. P. (1998) Science, 280:267; Reetz, M. T. et al. (1998) Angew Chem. 110:2792), fluorescence quenching (Cooper, A. C. et al. (1998) J. Am. Chem. Soc. 120:9971), microwell parallel reactions (Burgess, K. et al. (1996) Angew. Chem. 108:192; Senkan, S.M. (1998) Nature 394:350), and polymer-supported xe2x80x9cBeadxe2x80x9d methods (Cole, B. M. et al. (1996) Angew. Chem. 108:1776; Boussie, T. R. et al. (1998) Angew. Chem. 110:3472) have been applied with varying degrees of success. Only the polymer-supported bead methods have been applied to identify organometallic catalysts for polymerization reactions, the other methods being inapplicable for a variety of technical reasons. Even the polymer-supported bead method, when applied to polyolefin catalyst screening, suffers from a clumsy encoding procedure that limits its usefulness.
Catalyst screening strategies typically assay reaction rate or turnover number by rapid assay of the products of a catalyzed reaction. The emphasis is on the miniaturization and acceleration of methods used conventionally for product determination. For example, rate is correlated with heat release in the thermographic assay, which is appropriate for assays of overall catalytic activity. For polymerization reaction catalysts (Recent advances in new homogeneous Ziegler-Natta catalysts have been reviewed: Britovsek, G. J. P. et al. (1999) Angew. Chem. 111:448), on the other hand, overall catalytic activity is only one of several important catalyst properties for which high-throughput screens are needed. The key properties of polymerization products: average molecular weight (Mw, the weight-average molecular weight, or Mn, the number-average molecular weight) and molecular weight distribution (Mw/Mn, a measure of polydispersity because Mw emphasizes the heavier chains, while Mn emphasizes the lighter ones) are currently not accessible in any fast assay. The usual methods used to assess these properties of polymers, e.g., size-exclusion chromatography (also termed gel permeation chromatography or gpc), light scattering, viscosity, or colligative property measurement, require bulk samples and/or careful calibration, and are poorly suited to high-throughput screening.
The present invention provides methods for screening catalysts using mass spectrometric analysis of catalyst-bound intermediates in the catalytic cycle, or products of catalysis. The methods are applicable, in particular, to screening of organometallic compounds for catalytic function. Moreover, the methods are applicable, in particular, to screening for catalysts for polymerization reactions. More specifically, the methods employ a two stage (or two step) mass spectrometric detection method in which ions formed in a first stage ionization and which are linked to catalyst performance are selected and the catalyst associated with the selected ion is identified in a second stage employing tandem mass spectrometry. In specific embodiments, the screening methods of this invention avoid explicit encoding because the identity of the catalyst is implicitly contained in the product molecular mass (typically an intermediate product), since the catalyst (or a portion thereof) remains attached to the product.
The methods of this invention are particularly beneficial in screening for polymerization catalysts to avoid spectral congestion that can be created by the distribution of product oligomer and polymer lengths even for analysis of the polymerization products of a single catalyst species. Further, the screen, as applied to polymerization catalysts, is direct in that it assays polymer chain growth itself rather than a property which may be correlated with chain growth.
In the methods of this invention, one or more test catalysts are provided. The test catalysts are contacted with a selected reactant species under selected reaction conditions. The reagent species is a compound or mixture of compounds upon which the catalyst acts to generate a desired product. Reaction conditions are selected to promote a selected catalytic reaction. The catalytic reaction is quenched after a selected time sufficient to allow the selected reaction to proceed to generate product, e.g., for polymer chains to grow, and allow differentiation of catalyst activity. After quenching, the reaction mixture is introduced into the first stage of a tandem mass spectrometer, subjected to ionization, and mass analysis. Prior to introduction into the mass spectrometer, the quenched reaction mixture can optionally be subjected to partial purification, solvent removal, dilution, concentration, or chemical derivatization to improve analysis, remove impurities or the like.
Certain ions formed in the first stage of the tandem mass spectrometer are selected for introduction into the second stage of the spectrometer. Ions are selected which derive from the catalyst activity that is being screened. For example, in screens for polymerization catalysts ion mass selection can be employed, i.e. ions with mass/charge ratio (m/z) greater than a selected cutoff mass can be selected as derived from the best catalysts, e.g., those that promote the longest chains in the time given. The selected ions are introduced into the second stage of the mass spectrometer where they are subjected to a reaction to give daughter ions that allow identification of the catalyst which catalyzed formation of the products whose ions were selected from the first stage. For example, again in polymerization reactions, the selected high mass ions, associated with the longest polymer chains formed, are subjected in the second stage to reactive collisions with neutrals to generate daughter ions. Ion-molecule reactions, including collision-induced dissociation, can be employed to generate daughter ions. Preferred ion molecule reactions are those which cleave the product, e.g., the polymer chain, from its associated catalyst or portion of the catalyst, leaving an ion that can be directly, and preferably, uniquely related to the catalyst. Mass analysis of the daughter ions generated allows identification of the catalyst species responsible for the products from which the selected ions derive.
The test catalysts can be provided as a library encompassing a plurality of compounds spanning a range of structural variants to assess the relationship of structure to catalytic function. For example, a library of candidate polymerization catalysts is contacted with a selected monomer under reaction conditions (pH, temperature, solvent, etc.) that promote polymerization. In specific embodiments, the reaction mixture sample is introduced into the mass spectrometer in a manner that preserves association of the catalyst with the reaction product(s), e.g., the catalyst (or a portion thereof) remains associated with the growing polymer chain formed from reagent monomers in a polymerization reaction.
In specific embodiments, the mass spectrometric methods of this invention can also be employed to obtain bulk properties of polymers that result from the use of a catalyst. The average molecular weight and molecular weight distribution of all polymer chains, not just metal-bound (i.e., catalyst bound) polymers can be determined by the generation of kinetic data (as provided in Example 3). Distributions of odd chains (metal-bound oligomer chains with methyl endgroups) and even chains (metal bound oligomer chains with hydrogen endgroups) are observed in the mass spectrum after catalytic reaction. Fitting of the experimental odd/even distribution data with the general kinetic scheme for Ziegler-Natta polymerization yields absolute rates for initiation, propagation, and chain-transfer for a set of reaction conditions. These rates allow determination of average molecular weight and molecular weight distribution of products from catalytic reaction of screened catalysts without explicit preparation or isolation of bulk polymer. Average molecular weight and molecular weight distribution of polymeric products can be used as screening criteria for catalyst selection.
The method of this invention is particularly suited to screening of ionic and/or ion pair polymerization catalysts. A library of catalysts consisting of more than two distinct catalysts is contacted with an excess of monomer, usually ethylene, but which can be other simply substituted olefins, in organic solution. The reaction is then quenched with an additional ligand, such as CO, isocyanides, ethers, esters, phosphites, sulfoxides or other coordinating ligands, after polymerization has proceeded up to addition of a few hundred monomer units. The resulting quenched solution is then electrosprayed into a tandem mass spectrometer. The high mass ions which are associated with the catalyst (or a portion of the catalyst) linked to the longest polymer chains formed during the reaction are selected in the first stage of the mass spectrometer. These selected ions will be associated with the more active catalysts. The selected ions are then subjected in the second stage of the spectrometer to an ion-molecule reaction, e.g., collision-induced dissociation, to cleave off the oligomer/polymer chain from the catalyst. The daughter ion(s) remaining after the ion-molecule reaction is mass-analyzed in the second stage of the mass spectrometer identify the catalyst species responsible for the production of the highest molecular weight polymer chains. The drastic simplification of the mass spectrum by means of an ion-molecule reaction is a unique feature of this invention. Parent ion scans on a particular daughter mass allows the extraction of polymer distributions and the determination of kinetic parameters for one of the catalysts, in the presence of the others.